Submissions for variant NM_024747.6(HPS6):c.337C>T (p.Arg113Trp)

gnomAD frequency: 0.00222  dbSNP: rs371307947

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000374767	SCV000334098	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000369294	SCV000360061	uncertain significance	Hermansky-Pudlak syndrome 6	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000374767	SCV001566569	likely benign	not provided	2025-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000374767	SCV001811960	uncertain significance	not provided	2024-04-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 38091959, 29345414)
Genetic Services Laboratory, University of Chicago	RCV001820815	SCV002066688	uncertain significance	not specified	2019-05-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001820815	SCV002570948	likely benign	not specified	2024-11-07	criteria provided, single submitter	clinical testing	Variant summary: HPS6 c.337C>T (p.Arg113Trp) results in a non-conservative amino acid change located in the BLOC-2 complex member HPS6, N-terminal domain (IPR046823) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 1483646 control chromosomes, predominantly at a frequency of 0.0039 within the Non-Finnish European subpopulation in the gnomAD database, including 12 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6.2-fold of the estimated maximal expected allele frequency for a pathogenic variant in HPS6 causing Hermansky-Pudlak Syndrome phenotype (0.00063). c.337C>T has been reported in the literature in at least an individual affected with albinism (example: Lasseaux_2018). This report does not provide unequivocal conclusions about association of the variant with Hermansky-Pudlak Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29345414). ClinVar contains an entry for this variant (Variation ID: 282566). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000369294	SCV006054341	uncertain significance	Hermansky-Pudlak syndrome 6	2021-07-30	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003939961	SCV004756323	likely benign	HPS6-related disorder	2024-03-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).